mmg_233_2014_genetics_genomicsfandomcom-20200215-history
The Genetics of Thyroid
Thyroid Gland and Hormones The thyroid gland is one of the largest endocrine glands. It is made of two lobes and is located below the thyroid cartilage in the neck. The gland controls how quickly the body uses energy. It also makes proteins and controls how sensitive the body is to other hormones by producing thyroid hormones. These hormones are triiodothyronine (T3) and thyroxine (T4). These are vital for normal human physiology, because they effect growth, development, normal cognition, cardiovascular function, bone health, metabolism and energy balance. Thyroid hormones travel in the blood and allow the body to function in different ways. When there isn’t enough thyroid hormones present in the body, you feel tired and cold. People with thyroid conditions can also can weight, have dry skin and develop lumps in the neck. Lumps can form if the thyroid gland has to work extra to produce more hormones. Heritability Hypothyroidism is hereditary. People have increased chances to develop thyroid problems if other people in the family have hypothyroidism. They are also more susceptible to other thyroid diseases, such as hyperthyroidism, Hashimoto's thyroiditis, and thyroid cancer. Hashimoto's thyroiditis affects about 10 millon people in the United States, and it can result in hypothyroidism because the body's immune system will attack its own thyroid gland and create lower hormone production. The inheritance pattern of thyroid diseases is still unclear, because both genetic and environmental factors are involved. Causes It has recently been discovered that genetics play a prominent role in thyroid diseases. Although the field is still being studied, a few genes and factors have been discovered, which are believed to cause thyroid problems. The most common way people get hypothyroidism is through genetics. People with thyroid problems have genetic markers. These make them more susceptible to developing thyroid conditions. There are three ways genes are involved: 1) Congenital Hypothyroidism Some babies are born with hypothyroidism. This is called congenital hypothyroidism. Broken thyroid glands and glands that are not able to produce enough hormones cause this. Many DNA changes in genes cause broken glands. Several genes work together to form thyroid glands. Mutations, deletions and insertions in the DNA can disrupt proper thyroid gland formation, which causes congenital hypothyroidism. 2) Incorrect number of chromosomes Missing chromosomes can also cause hypothyroidism. Both groups can have hypothyroidism, so genes on different chromosomes can cause the problem. 3) Autoimmune Response Sometimes the body attacks its own thyroid gland, which is an autoimmune response. If the attack is a long one, the gland cannot produce thyroid hormones at all, which causes thyroid conditions. All the genes that are involved in thyroid gland formation are in the Major Histocompatibility Complex (MHC). Some of the genes have DNA changes in people with autoimmune hypothyroidism, which make them more susceptible to thyroid diseases. Autoimmune diseases can causes the overproduction of thyroid hormones as well. Graves’ disease overproduces thyroid hormones so the body ends up attacking itself. Although some people have genetic markers that increase their chances of getting thyroid diseases, problems might never form. This is because, like many other complex diseases, a combination of genes and the environment are what lead to hypothyroidism. Genes Involved Circulating TSH, or free T4 and T3 hormones, vary greater inter-individual rather than intra-individual. A significant portion of TSH variation is genetically derived. Polymorphisms within three genes are associated with thyroid function in healthy subjects at genome-wide levels of significance: 1) Phosphodiesterase 8B (PDE8B) 2) Iodothyronine deiodinase 1 (DIO1) 3) F-actin-capping protein subunit beta (CAPZB) Each of these genes contributes to a small amount of variability of hormone concentrations. This means that there are more genes and mechanisms of genetic influence, which cause hypothyroidism, that have not been discovered yet. DIO1 and the TSH receptor have been found to influence thyroid function. They influence a wide range of clinical and developmental phenotypes from bone health to neurological development. This will help with future research regarding the complex action of thyroid hormones on individual tissues. A polymorphism in the TSH receptor gene is associated with TSH at genome wide significance levels and in different populations. Genetics play an important role in the determination of thyroid hormones and thyrotropin (TSH) concentrations. They also play a prominent role in susceptibility to autoimmune thyroid disease. Heritability studies suggest that about 67% of circulating thyroid hormone and TSH concentrations are genetically determined. This suggests a genetic basis for varying intra-individual and inter-individual levels. This also suggests that there is a genetic set point. Autoimmune Thyroid Disease Autoimmune thyroid disease (AITD) generally runs within families. It comprises of a series of interrelation conditions. These include Grave’s disease (GD), Hashimoto’s thyroditis, atrophic autoimmune hypothyroidism, postpartum thyroiditis (PPT), and thyroid-associated orbitipathy (TAO). These can occur at the same time in different combinations. Furthermore, different AITD phenotypes can occur at the same time in the same body. The clustering of different AITD phenotypes within individuals shows that the conditions have a common pathophysiological basis. AITDs are the most common autoimmune disorders. It affects 2-4% of women and about 1% of men. Chances of AITD also increase with age. The currently accepted model for pathogenesis of AITD suggests that there is an inherited predisposition to autoimmunity, along with addition environmental and hormonal factors that can trigger the development of a thyroid disease. Environmental factors, such as cigarette smoking and adverse psychosocial events, can cause development. Additionally, modulation in animal models of AITD with gonadal steroids, amerlioration of GD during pregnancy, and PPT occurrence show that sex steroids play an important role in AITD disorders. A recent study that was based on data from a large twin study suggests that 79% of predisposition to GD is because of genetic factors. The rest is environmental and hormonal influences. Environmental Factors Genes and DNA aren’t the only factors when it comes to developing hypothyroidism. Conditions are influenced heavily by lifestyle factors. This means that heart diseases, cancer, Parkinson’s Alzheimer’s and arthritis can be causes as well. If such conditions can be prevented, the genetic marker that makes people susceptible to hypothyroidism can be prevented from activating. Treatment Hypothyroidism can be treated with hormone replacement therapy. This means patients must take synthetic forms of the thyroid hormone everyday to reduce symptoms. If treatment is started right away in those born with cognitive thyroid, the babies will develop normally. References 1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219766/ 2. http://press.endocrine.org/doi/full/10.1210/jc.2002-020492?view=long&pmid=12466323& 3. http://genetics.thetech.org/ask/ask182